Pancreatic cancer is one of the most devastating human cancers and is the fourth leading cause of overall cancer-related mortality in the United States. Currently, there is no clinically effective therapy for pancreatic cancer. The only chance for complete recovery is surgical resection; however, only 15-20% of patients have a resectable tumor, and of those only 20% survive up to five years after surgery. Pancreatic cancer metastasizes early and extensively, and invades surrounding tissues aggressively. In addition to its rapid progression, nearly all conventional chemotherapies and radiation treatments are ineffective against pancreatic cancer. Even when diagnosed early, patients with pancreatic cancer have <1% chance of a complete recovery. The high resistance of pancreatic cancer to available conventional chemotherapies along with its aggressive nature highlights the urgent need to develop novel effective adjunct therapies to combat this devastating cancer.
Pancreatic cancer cells are known to be remarkably tolerant to nutrient and oxygen deprivation under hypovascular conditions. Hypoxic and nutrient-deprived pancreatic cells which have adapted to survive under these conditions in tumors, both elude conventional anticancer therapies and also drive forward disease progression. Therefore, agents that eliminate the ability of cancer cells to survive under nutrient starvation conditions are potentially useful anticancer agents. In 2006, a coumarin-based natural product, angelmarin, was isolated from the root of the Japanese medicinal plant, Angelica pubescens. Angelmarin was found to exhibit cytotoxicity of 0.01 μg/mL against the pancreatic cancer cell line PANC-1 under nutrient starvation conditions within 24 hours.
Angelmarin is a coumarin-based natural product with a molecular formula of C23H20O6 and a chemical name of 11-O-(p-hydroxy-cinnamoyl) columbianetin. Coumarins are ubiquitous structures present in a large number of natural compounds comprising a broad range of powerful physiological activities including anticancer, anti-viral, antifungal, anti-inflammatory, antioxidant, anticoagulant, antibacterial, antitubercular, and analgesic activities. Because of their diverse pharmacological properties, coumarins have attracted intense interest in recent years. Among these properties, the cytotoxic activities of coumarins have been the most extensively studied and coumarin compounds have served as valuable leads for further design and synthesis of more active anticancer analogues.